Abstract Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7 , with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10 −4 ) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10 −4 ). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10 −3 ), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10 −8 ). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10 −5 ). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.
Background Little is known about the short and long-term therapeutic management of asthmatic children. The aim of this study was to assess the prescribing patterns of antiasthma drugs in primary care. Methods This is a retrospective cohort study performed between January 2011 and December 2017 using the EGB (Echantillon Généraliste de Bénéficiaires) database, a 1/97th sample of the French national healthcare insurance system. Claims data for all individuals aged from 5 to 18 years‘ old who had received at least one antiasthma drug in the study period without any delivery in the previous 24 months and with 24 months of follow-up after first delivery, were analysed. Results A total of 7,680 children and adolescents (68.6% aged 5–11, 31.4% aged 12–18 years) were delivered at least one antiasthma drug (ATC code R03) during study period. The majority (66%) did not redeem another prescription in the following year (occasional users), when 18.4% redeemed prescriptions twice (low users) and 15.6% ≥3 times (high users). Most users (67%) were delivered only one class of R03 per dispensing in the first year and short-acting β2-agonists (SABAs) were the most frequently dispensed drugs. However, 33.4% of users were not prescribed SABAs. During the second year, only 27% of first-year users redeemed R03 prescriptions: 15.8% among occasional users, 35.5% of low users and 64.7% of high users. Among low and high first-year users who redeemed R03 drugs during the second year, 39.7% did not use inhaled corticoids alone or in association to LABAs. Conclusions A high proportion of children and adolescents that used antiasthmatic drugs, even on a regular basis, were not prescribed these drugs in the long term. This finding may correspond either to the widespread use of antiasthmatic drugs in indications other than asthma or to an important undertreatment of asthmatic children and adolescents. Disclosure(s) Nothing to disclose
Les sous-types moléculaires de cancer du sein ont des statuts axillaires différents. Un nouveau nomogramme incluant l'interaction entre les récepteurs aux oestrogènes (RO) et le statut HER2 a récemment été publié et permet d'identifier, avant la chirurgie, les patientes ayant un haut risque d'atteinte du ganglion sentinelle axillaire (GS) [1]. L'objectif de notre étude était de valider ce modèle sur une population indépendante.
